The plasma protein properdin was discovered more than a half-century ago in connection with the alternative pathway (AP) of complement activation. Although it was initially regarded as an initiator of the AP complement, the currently held view of properdin function is that it acts as a stabilizer of the AP C3 convertase C3bBb, playing a facilitating but not essential role in AP complement activation. We have generated preliminary data to show that properdin is critical for AP complement activation on autologous tissues, thus challenging the present view on properdin function and identifying it as a potential therapeutic target in complement injury. In this proposal, we will define the role of properdin in AP complement activation and tissue injury and explore the strategy of anti-properdin therapy in murine models of complement-dependent disease. Our specific aims are: 1. To generate tissue-specific properdin knockout mice and anti-mouse properdin antibodies and determine the source and turnover of properdin in vivo. 2. To test the role of properdin in murine models of arthritis and evaluate the efficacy of anti-properdin therapy in arthritis;3.To test the role of properdin in the pathogenesis of atypical hemolytic uremic syndrome (aHUS) and evaluate the efficacy of anti-properdin therapy in aHUS. These studies will shed new light on the role and mechanism action of properdin and facilitate the development of novel anti-complement therapies for arthritis, aHUS and other AP complement-mediated pathologies. PUBLIC HEALTH RELEVANCE: This project studies the role of a protein called properdin in two immune-mediated diseases affecting the joints (arthritis) and the kidney (aHUS, for atypical hemolytic uremic syndrome). We will use the mouse as a model to test the hypothesis that properdin is involved in the pathogenesis of arthritis and aHUS and will develop monoclonal antibodies against properdin to treat these two diseases. These pre-clinical studies may lead to the development of anti-properdin agents as therapeutic drugs for human patients suffering from these conditions.